Anti-Inflammatory Effects of Marine-Derived Resorcylic Acid Lactone Derivatives in Ulcerative Colitis via the MAPK/ERK Pathway

TL;DR

This study shows that a marine-derived compound, compound 4, reduces inflammation in ulcerative colitis by inhibiting the MAPK/ERK pathway.

Contribution

The study identifies compound 4 as a new anti-inflammatory agent for UC through the MAPK/ERK pathway, a novel mechanism for RAL derivatives.

Findings

Compound 4 reduces inflammation in macrophages and UC models by inhibiting the MAPK/ERK pathway.

Compound 4 alleviates UC symptoms like body weight loss and colon shortening in DSS-induced models.

Compound 4 protects intestinal epithelial integrity and reduces pro-inflammatory cytokine production.

Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent inflammation of the colonic mucosa, and there is currently a lack of safe and effective treatment drugs. Resorcylic acid lactones (RALs) are a natural product that have been reported to have anti-inflammatory effects. However, the mechanism of whether RALs can treat UC and their anti-inflammatory effects remains underexplored. In this study, three new RAL derivatives, Penicillactones A–C (1–3), along with seven known analogs (4–10), were isolated from the marine fungus Penicillium sp. HN20. The structures of compounds 1–3 were elucidated by spectroscopic methods, 13C NMR theoretical calculations, and ECD analysis. Among these, compound 4 exhibited potent anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages. In a dextran sulfate sodium (DSS)-induced UC model, compound 4 alleviated body weight loss, disease activity, colon shortening, and spleen enlargement, and protected intestinal epithelial integrity. Mechanistic studies revealed that compound 4 primarily exerts its effects by downregulating the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (MAPK/ERK) signaling pathway, inhibiting pro-inflammatory cytokine production. Collectively, these findings provide the first evidence that marine-derived RAL derivatives exert anti-inflammatory effects by inhibiting the MAPK/ERK pathway, highlighting compound 4 as a promising therapeutic candidate for inflammation and UC.

Figures